AJP - Cell Physiology, Vol 267, Issue 5 C1185-C1195, Copyright © 1994 by American Physiological Society

ARTICLES

Endothelin receptors in human smooth muscle cells: antagonist potency differs on agonist-evoked responses

J. R. Wu-Wong, W. J. Chiou, Z. J. Huang, M. J. Vidal and T. J. Opgenorth
Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, Illinois 60064.

The present study characterized endothelin (ET) receptors in human pericardium smooth muscle cells (HPSMC) and examined the potency of antagonists on ET-evoked signal transduction and DNA synthesis. HPSMC contain both ETA and ETB receptors. ET-1 binding was completely inhibited by a nonselective antagonist (Ro-46-2005) or a combination of ETA-selective and ETB-selective ligands (BQ-123 and ET-3). The molecular masses for ETA and ETB receptors were 69 and 42 kDa, respectively. ET-1, but not ET-3, stimulated phosphatidylinositol hydrolysis and arachidonic acid release in a dose- and time-dependent manner, reaching a plateau within 20-40 min. These immediate effects of ET-1 on signal transduction were completely inhibited by 1 microM, BQ-123, ET-1, but not ET-3, stimulated DNA synthesis in a dose-dependent manner, and the effect became prominent after 24 h. BQ-123 (1 microM) or Ro-46-2005 (10 microM) did not completely inhibit this mitogenic effect of ET-1. The reduced potency of BQ-123 and Ro-46-2005 on the delayed effect of ET-1 was not the result of ligand degradation or a difference in receptor internalization; rather, the decrease in potency was due to the fact that antagonist binding was more reversible than ET-1 binding.

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